Plasmodium vivax malaria contributes to a large burden of malaria morbidity owing to its widespread global distribution, the increasing prevalence of drug-resistant strains and most importantly, infections with Pv cause severe clinical syndromes. Plasmodium vivax accounts for 12.4% of infections acquired in Africa and 70-90% of infections acquired in Asia and the Americas. More cases of Pv are now reported than any other malaria species for active duty or returning soldiers. Because of increasing drug resistance to Pv, lethal cases and replapsing behavior of Pv, development of Pv vaccine is a major priority of the Military Infectious Disease Research Program. One the leading Pv vaccine candidates is P. vivax Duffy binding protein region II (PvDBPII). This protein is expressed at the parasite's cellular surface and binds the host red cell's Duffy antigen (Fy) that facilitates erythrocyte invasion. Other human malaria such as P. falciparum, have several different Duffy Binding Protein-like genes that facilitate the use o alternative receptors for merozoite invasion, however the almost exclusive dependence of PvDBPII and Duffy antigen for Pv invasion of erythrocytes a critical weakness and makes the Pv DBP ligand an ideal target for vaccine development. Substantial challenges remain for use PvDBPII as a vaccine, including its high degree of polymorphism, its weak immunogenicity and a lack of understanding as regards to the specific portion of the molecule engendering the strongest blocking or protective responses. This proposal builds on observations from our current project. First, we have identified a subset of individuals in endemic areas who acquire high titers of functional antibodies described above that block binding to multiple PvDBPII variants. Mapping of the functional human Abs to specific regions of PvDBPII may help to identify a strain-transcending vaccine. Second, polyclonal and monoclonal antibodies generated in different animals that block binding of PvDBPII to Fy preferentially recognize a relatively conserved sub-domain of PvDBPII that could facilitate development of a vaccine. Third, we have shown that the major polymorphism in Fy (FybFya, Asp42Gly) is associated with both diminished binding of PvDBPII and a reduced risk of clinical Pv in humans. We found that both naturally acquired and artificially induced Abs directed to PvDBPII more effectively blocked its binding to Fya as compared to Fyb erythrocytes, indicating host Fy genotype may be important vaccine efficacy. Aim 1. To identify epitopes on PvDBPII recognized by strain-transcending neutralizing antibodies. Aim 2. To develop vaccine approaches to elicit strain-transcending blocking/invasion inhibitory antibodies to PvDBPII. Aim 3. To determine the role of the Duffy Fya as compared to Fyb phenotype in functional immune responses to PvDBPII in vitro and in vivo.